Transcription factor binding activity is the primary driver of noise in gene expression

Abstract

AbstractNoise in expression of individual genes gives rise to variations in activity of cellular pathways and generates phenotypic heterogeneity. Phenotypic heterogeneity has important implications for antibiotic persistence, mutation penetrance, cancer growth and therapy resistance. Even though the role of specific factors such as presence of TATA box sequence in the promoter of a gene and promoter nucleosome occupancy in noise regulation have been studied, the ability of these factors to predict noise remains unknown. Here we build an integrated quantitative statistical model for gene expression noise in yeast and show that the number of regulating transcription factors and their binding activity are the primary drivers of noise. Combining our model with stochastic simulations, we specifically show that the binding activity arising from competition and cooperation among TFs for binding to the promoter region can drive noise. Our work uncovers a general process of noise regulation that arises out of the dynamic nature of gene regulation that is not dependent on specific transcription factor or specific promoter sequence and thus can be extended across biological systems.